Crystals of aniline pyrimidine compound serving as egfr inhibitor

Abstract

The present application belongs to the field of medicinal chemistry, and relates to crystals of an aniline pyrimidine compound serving as an EGFR inhibitor. Specifically, the present application relates to crystal A, crystal B and crystal C of N-(2-((2-(dimethyl amino)ethyl)(methyl)amino)-4-methoxy-5-(4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-base)pyrimidine-2-base amino)phenyl)acrylamide (formula I) hydrochloride, and also relates to the method for preparing the crystal A, the crystal B and the crystal C, a crystal composition comprising the crystal A, the crystal B, and the crystal C, a pharmaceutical composition comprising the crystal A, the crystal B and the crystal C or the crystal composition thereof, and medical uses thereof. The crystal A, the crystal B and the crystal C in the present application has the advantages of high purity, high crystallization degree, good stability and the like.

1 . A crystal A of the hydrochloride of a compound represented by formula I: 
       
         
           
           
               
               
           
         
         wherein an X-ray diffraction pattern of the crystal A of the hydrochloride of the compound represented by formula I has diffraction peaks at 2θ of 8.96°±0.2°, 14.11°±0.2°, 14.87°+0.2°, 16.52°+0.2°, 18.67°±0.2°, 21.93°±0.2° and 27.09°±0.2°; typically has diffraction peaks at 2θ of 8.33°±0.2°, 8.96°±0.2°, 12.16°+0.2°, 14.11°±0.2°, 14.87°±0.2°, 16.52°±0.2°, 17.66°±0.2°, 18.67°±0.2°, 21.93°+0.2° and 27.09°+0.2°; more typically has diffraction peaks at 2θ of 8.33°±0.2°, 8.96°±0.2°, 11.74°±0.2°, 12.16°±0.2°, 14.11°±0.2°, 14.87°±0.2°, 16.52°±0.2°, 17.66°±0.2°, 18.23°±0.2°, 18.67°±0.2°, 21.93°±0.2°, 22.65°±0.2° and 27.09°±0.2°; and further typically has diffraction peaks at 2θ of 8.33°±0.2°, 8.96°±0.2°, 11.74°±0.2°, 12.16°±0.2°, 14.11°±0.2°, 14.87°±0.2°, 16.52°±0.2°, 17.66°±0.2°, 18.23°±0.2°, 18.67°±0.2°, 19.48°±0.2°, 19.92°+0.2°, 21.93°±0.2°, 22.65°±0.2°, 24.95°±0.2°, 27.09°+0.2° and 27.55°±0.2°. 
       
     
     
         2 . The crystal A of the hydrochloride of the compound represented by formula I according to  claim 1 , wherein its DSC spectrum has a peak at 271° C. 
     
     
         3 . A method for preparing the crystal A of the hydrochloride of the compound represented by formula I according to  claim 1 , comprising the following steps:
 1) contacting the compound represented by formula I with hydrochloric acid; and   2) crystallizing the hydrochloride of the compound represented by formula I from a crystallization solvent, and optionally filtrating the obtained crystal;   wherein the crystallization solvent is selected from acetonitrile, methanol, isopropanol, or a mixture of ethanol and water.   
     
     
         4 . A crystalline composition, wherein the crystal A of the hydrochloride of the compound represented by formula I according to  claim 1  accounts for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition. 
     
     
         5 . A pharmaceutical composition, comprising a therapeutically effective amount of the crystal A of the hydrochloride of the compound represented by formula I according to  claim 1 . 
     
     
         6 . A method for treating an EGFR-mediated disease, comprising administering to a mammal in need thereof a therapeutically effective amount of the crystal A of the hydrochloride of the compound represented by formula I according to  claim 1 . 
     
     
         7 . A crystal B of the hydrochloride of a compound represented by formula I: 
       
         
           
           
               
               
           
         
         wherein an X-ray diffraction pattern of the crystal B of the hydrochloride of the compound represented by formula I has diffraction peaks at 2θ of 9.17°±0.2°, 9.93°±0.2°, 14.07°+0.2°, 20.31°±0.2°, 21.44°±0.2° and 26.10°±0.2°; typically has diffraction peaks at 2θ of 9.17°+0.2°, 9.93°±0.2°, 10.65°±0.2°, 13.46°±0.2°, 14.07°±0.2°, 20.31°±0.2°, 21.44°+0.2°, 22.33°±0.2°, 24.93°±0.2° and 26.10°±0.2°; and more typically has diffraction peaks at 2θ of 6.71°±0.2°, 9.17°±0.2°, 9.93°±0.2°, 10.65°±0.2°, 11.44°±0.2°, 13.46°±0.2°, 14.07°±0.2°, 18.94°±0.2°, 20.31°±0.2°, 21.44°±0.2°, 21.66°±0.2°, 22.33°±0.2°, 24.93°±0.2°, 25.73°±0.2° and 26.10°±0.2°. 
       
     
     
         8 . The crystal B of the hydrochloride of the compound represented by formula I according to  claim 7 , wherein its DSC spectrum has a peak at 259° C. 
     
     
         9 . A method for preparing the crystal B of the hydrochloride of the compound represented by formula I according to  claim 7 , comprising the following steps:
 1) contacting the compound represented by formula I with hydrochloric acid; and   2) crystallizing the hydrochloride of the compound represented by formula I from a crystallization solvent, and optionally filtrating the obtained crystal;   wherein the crystallization solvent is ethanol.   
     
     
         10 . A crystalline composition, wherein the crystal B of the hydrochloride of the compound represented by formula I according to  claim 7  accounts for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition. 
     
     
         11 . A pharmaceutical composition, comprising a therapeutically effective amount of the crystal B of the hydrochloride of the compound represented by formula I according to  claim 7 . 
     
     
         12 . A method for treating an EGFR-mediated disease, comprising administering to a mammal in need thereof a therapeutically effective amount of the crystal B of the hydrochloride of the compound represented by formula I according to  claim 7 . 
     
     
         13 . A crystal C of the hydrochloride of a compound represented by formula I: 
       
         
           
           
               
               
           
         
         wherein an X-ray diffraction pattern of the crystal C of the hydrochloride of the compound represented by formula I has diffraction peaks at 2θ of 7.68°±0.2°, 8.21°±0.2°, 10.89°±0.2°, 15.95°±0.2°, 19.10°±0.2°, 20.52°±0.2° and 21.54°±0.2°; typically has diffraction peaks at 2θ of 7.68°±0.2°, 8.21°±0.2°, 9.55°±0.2°, 10.89°±0.2°, 15.95°±0.2°, 19.10°±0.2°, 20.52°±0.2°, 21.08°±0.2°, 21.54°±0.2° and 28.22°±0.2°; and more typically has diffraction peaks at 2θ of 7.68°±0.2°, 8.21°±0.2°, 9.55°±0.2°, 10.89°±0.2°, 14.22°±0.2°, 14.95°±0.2°, 15.95°±0.2°, 19.10°±0.2°, 20.52°±0.2°, 21.08°±0.2°, 21.54°±0.2°, 23.05°±0.2°, 26.23°±0.2° and 28.22°±0.2°. 
       
     
     
         14 . The crystal C of the hydrochloride of the compound represented by formula I according to  claim 13 , wherein its DSC spectrum has peaks at 175° C. and 262° C. 
     
     
         15 . A method for preparing the crystal C of the hydrochloride of the compound represented by formula I according to  claim 13 , comprising the following steps:
 1) contacting the compound represented by formula I with hydrochloric acid; and   2) crystallizing the hydrochloride of the compound represented by formula I from a crystallization solvent, and optionally filtrating the obtained crystal;   wherein the crystallization solvent is selected from tetrahydrofuran, acetone, or dioxane.   
     
     
         16 . A crystalline composition, wherein the crystal C of the hydrochloride of the compound represented by formula I according to  claim 13  accounts for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, by weight of the crystalline composition. 
     
     
         17 . A pharmaceutical composition, comprising a therapeutically effective amount of the crystal C of the hydrochloride of the compound represented by formula I according to  claim 13 . 
     
     
         18 . A method for treating an EGFR-mediated disease, comprising administering to a mammal in need thereof a therapeutically effective amount of the crystal C of the hydrochloride of the compound represented by formula I according to  claim 13 .